Cutaneous malignant melanoma (CMM) incidence is rising, accounting for approximately 4% of cancer diagnoses in U.S. Recently, a novel CMM susceptibility locus was identified on chromosome 1 (1p22). To identify this gene Aim 1, we will use a multidisciplinary approach to comprehensively identify, prioritize, and screen genes within the critical region. We will construct a custom oligonucleotide microarray with probes representing all evolutionarily conserved sequence at 1p22 and assay expression in melanocytes and melanoma cell lines to identify all expressed genes in the region. We will use these arrays for CGH to screen for deletions in familial CMM patients and sporadic melanoma cell lines. We will SNP-genotype our families and perform a linkage disequilibrium based association study to narrow the 1p22 critical region. Based on these experiments, we will prioritize 1p22 candidates for high-throughput mutation screening. Once the CMM susceptibility gene is identified, we will look for genotype-genotype correlation, testing the hypothesis that Iow-penetrance genetic CMM risk factors act as modifiers to the penetrance of 1p22 mutations (Aim 2). Finally, we will determine the prevalence of 1p22 mutations in sporadic melanoma cell lines and tumors (Aim 3).